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| Title | Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity. |
|---|---|
| Journal, issue, pages | Nature, Year 2026 |
| Publish date | Mar 25, 2026 |
 Authors | Sam O Kleeman / Kevin Michalski / Xiang Zhao / Ruben Steigerwald / Miriam Ferrer / Llewelyn Levett / Ethan Ertel / Austin Schultz / Noriko Simorowski / Pamela Moody / Tse-Luen Wee / Cristina Valente / Sharon Fox / Mateusz Makuch / Selina Thomsen / Ruby Harrison / Claire Regan / Jonathan Preall / Qing Gao / Dennis Thomas / Jill Habel / Rachel Rubino / Sarosh Irani / Hiro Furukawa / Tobias Janowitz /   |
| PubMed Abstract | Autoimmunity and anti-cancer immunity lie on the same biological continuum, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is ...Autoimmunity and anti-cancer immunity lie on the same biological continuum, but their link remains obscure. The paraneoplastic neurological syndrome ANRE (anti-NMDA receptor (NMDAR) encephalitis) is a paradigm for their connectivity, given that intratumoural NMDAR expression is correlated with the generation of anti-NMDAR antibodies. Here we verify ectopic expression of GluN1 and GluN2B NMDAR subunits in triple-negative breast cancer (TNBC) and model this using orthotopic TNBC tumours with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce the recruitment of B cells and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoural B cell phylogenies and cryogenic electron microscopy structural analyses demonstrate that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE. We further identify a correlation between intratumoural NMDAR expression and anti-NMDAR antibody titres in patients with TNBC. Taken together, our data establish a direct connection between intratumoural NMDAR expression, antibody maturation and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease after maturation, revealing a mechanistic trade-off between cancer immunity and neurotoxicity. |
 External links | Nature / PubMed:41882353 |
| Methods | EM (single particle) |
| Resolution | 3.09 - 4.55 Å |
| Structure data | EMDB-75112, PDB-10en: EMDB-75120, PDB-10ev: EMDB-75121, PDB-10ex: EMDB-75122, PDB-10ey: EMDB-75123, PDB-10ez: EMDB-75127, PDB-10fd: EMDB-75128, PDB-10fe: EMDB-75129, PDB-10ff: EMDB-75134, PDB-10fl: EMDB-75136, PDB-10fn: EMDB-75138, PDB-10fo: |
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 Keywords | SIGNALING PROTEIN/Immune System / NMDAR / antibody / SIGNALING PROTEIN / SIGNALING PROTEIN-Immune System complex / SIGNALING PROTEIN/Imuune System / SIGNALING PROTEIN-Imuune System complex |
homo sapiens (human)
mus musculus (house mouse)